Examining biomarkers in the context of Schizophrenia

A study published in Translational Psychiatry, shows using cultured cells from patients with psychotic disorders, such as schizophrenia, to investigate abnormalities in nerve connections in the brain may lead to new treatments. The study depicted that there was a strong correlation between the findings in the cells in culture-grown outside the body in a controlled environment, and findings from brain imaging performed on the very same human participants. In a cross-study done in two years among thirty-seven subjects. There was a loss of regional matter in the thalamus in the schizophrenic patient in contrast to the normal brained subjects. The control and Schizophrenic are different in the way that there is a correlation between changing the shape and positive symptoms across time. The longitudinal changes in the Pulvinar are correlated with the prefrontal gyrus and some parietal regions in the brain. Extending the study and looking at non-psychotic sibling (of the psychotic-subject) showed that there was some deformity in the prefrontal cortex. Similarly the measure of shape of the thalamus was in the premedical range which showed that it may be a phenotype.  

Moreover, the basal ganglia had a similar arrangement where the schizophrenic is more severely affected. Longitudinal studies may be difficult especially since there may be inconsistencies in shape findings. However, some posterior and anterior does have some consistencies. The challenges of schizophrenia is that it is highly heterogeneous. There is genetic variation, and there are different methods of neuro-imaging studies. Moreover, through Enigma, one can use data from numerous sites and compute medical curve and complete is a meta-analysis, a standardized, uniform study.  The thalamus, hippocampus and amygdala show strong inward and outward deformity for each structure. In schizophrenia, there is both positive and negative patterns in the structures which suggests that its part of a network. All in all, "the findings are important, because if the health of cells in culture reflects the health of the same cells in a human brain, we may be able to create a better model for studying psychotic disorders," said the study's senior author, Bruce M. Cohen, MD, PhD, director of McLean Hospital's Program for Neuropsychiatric Research. 

          Schizophrenia is a severe mental disorder which is characterized with abnormal interpretation of reality, breakdown of thought process, and emotional responsiveness. Positive symptoms may include Paranoia, dilutions; Negative Symptoms may include Incoherence, frequent derailment, and mood symptoms are depression, labile mood, and cognitively suffer from a wide spectrum of symptoms. There is a frontal loss of tissue in the hippocampus and the tail is bending forward (red region on a plot). 

"The volumes are different by 5% from normal (not statistically significant) however the shape difference is statistically significant which is related to the amount of the disorganized score in the patient. Therefore the more deformity in the shape of the hippocampus the more severe the schizophrenic patient is. Furthermore, thalamic volume does significantly decrease and there is loss in cultivar, and anterior region of the dorsal thalamus which reflects the post Martim status."

It has a different distribution from the NADPH-d Neurons in contrast to a normal brain-there is a pathological difference in the hippocampus to study schizophrenia. The total number of neurons and volume of neurosis reduced in the thalamic nuclei in the hippocampus. The Basal ganglia and Amygdala also has a reduced density in the regions. However, other groups found opposite results- there is a tendency to find an increased neurons in the individual’s brain. This is found and is validated with imaging studies. There is pathological support to find the number of neurons in the brain. Thus, whole volume shapes were not as descriptive as studying the shape difference when determine localized loss of grey matter in the basal ganglia.

Schizophrenia is a disorganization of networks in which the subcortical shape measures and candidate Biomarkers for the disease, and the cortex are preferentially affected. This is the first step to reason if the different shape profile can relate to different patient and their treatment type. Challenges going forward are that the brain behaviors and not simple correlations and obtaining predictors for schizophrenia and may be difficult due to the heterogeneity. However, these challenges are used to learn how to process and better analyze data. Lastly, the premise of the project is about homology- it rests on the premise that the subject is similar to the template and it can be further used to define tumor templates, or to change the map for other neurodegenerative diseases. One can potentially use the results and the research to develop novel and more effective interventions for other psychotic disorders which are not yet known- i.e. causation of Alzheimer’s disease.

  Lastly, neuroimaging is used to understand differences between groups of people. The brain is connected to the rest of the cortex through the pathways. Deep structure of the brain: Hippocampus, amygdala, thalamus, basal ganglia. Pathological studies provides the reason to study pathways-The hippocampus does have connection to the parietal cortex. There are numerous brain connections; the Corticobasal-ganglia and thalamo-cortical loops have direct and excitatory connections with the connections. Through deep brain studies and the study of the shape may result in new findings. The objective is to look at what is normal and characterize what abnormal is. Identifying what is normal and then presenting it with abnormal data; one can determine the intensity of the difference between both entities. Through mapping, one is able to compute intensity based large deformation mapping. Mapping that is based on the intensity of Phi. Later once can compose segmentation of the atlas with the mapping to get segmentation of the primary image. One can map right and left hand if they start close together, if a single ligament is offset, mapping is not possible if there is an orientation deficiency. Therefore, many researchers would manually place landmarks through Free Surfer and paired it with FS+ LDDMM which creates a perfect procedure for segmentation. Mapping a variety of atlases to the template, one minimizes errors by increasing the variability. Starting with a multi variable atlas, one would have to pick top picks to represent the atlas and remap for the population-this technique improves segmentation. To understand the data, one can calculate the mean, standard deviation, and covariance. Then calculating the "p values" or differences across different environments which will allow one to distinguish normal from abnormal.

References:

Donna L. McPhie, Ralda Nehme, Caitlin Ravichandran, Suzann M. Babb, Sulagna Dia Ghosh, Alexandra Staskus, Amy Kalinowski, Rupinderjit Kaur, Panagiotis Douvaras, Fei Du, Dost Ongur, Valentina Fossati, Kevin Eggan, Bruce M. Cohen. Oligodendrocyte differentiation of induced pluripotent stem cells derived from subjects with schizophrenias implicate abnormalities in development. Translational Psychiatry, 2018; 8 (1) DOI: 10.1038/s41398-018-0284-6

Johns Hopkins Medicine. "Schizophrenia linked with abnormal immune response to Epstein-Barr virus." ScienceDaily. ScienceDaily, 9 January 2019. <www.sciencedaily.com/releases/2019/01/190109090911.htm>.

McLean Hospital. "In vitro cell culture findings could lead to novel interventions for Schizophrenia." ScienceDaily. ScienceDaily, 30 November 2018. <www.sciencedaily.com/releases/2018/11/181130175052.htm>.

University of Nevada, Las Vegas. "Keep it complex: Study shows that previous research oversimplified Schizophrenia symptoms." ScienceDaily. ScienceDaily, 27 November 2018. <www.sciencedaily.com/releases/2018/11/181127171402.htm>.